The effects of N-6 polyunsaturated fatty acid supplementation on the lipid composition and atherogenesis in mouse models of atherosclerosis

Despite numerous studies, the precise role of dietary n-6 polyunsaturated fatty acids in the pathogenesis of atherosclerosis remains controversial. It has been shown that feeding an n-6-enriched diet resulted in decreased atherosclerosis in African green monkeys and was associated with a reduction in LDL levels. However, other authors reported that n-6 supplementation increased the oxidative stress and the susceptibility of LDL to undergo in vitro oxidation, thus potentially enhancing atherosclerosis. The present study was designed to investigate the effect of dietary supplementation of n-6 polyunsaturated fats (safflower oil), as compared with a saturated fat-rich diet (Paigen), on the blood lipid profile and atherosclerosis in two mouse models. In the first experiment, female C57BL/6 mice (n=23–30 per group) were fed a cholate containing Paigen diet, a safflower oil-rich diet (with cholate), or normal chow for 15 weeks. No significant differences between the high fat diet groups were evident with respect to total cholesterol, LDL, HDL or triglyceride levels. The extent of aortic sinus fatty streaks did not differ significantly between the two groups. In the second experiment, LDL-receptor-deficient (LDL-RD) mice (n=20–30 per group) were randomized into similar dietary regimens. Mice consuming a safflower oil-enriched diet developed significantly less atherosclerosis, in comparison with Paigen diet-fed mice. A reduction in LDL levels, although not of a similar magnitude as the reduction in atherosclerosis, was evident in the safflower oil-fed mice when compared to the Paigen diet-fed littermates. In both mouse models of atherosclerosis, LDL isolated from the plasma of mice on the n-6 polyunsaturated diet was rendered slightly more susceptible to oxidation in vitro, as indicated by a shorter lag period for diene formation. Thus, the effects of n-6 fatty acids on the lipoprotein composition and other potential influences may have contributed to the anti-atherogenic effect in the LDL-RD mouse model.     

Evaluation of a new equation for LDL-c estimation and prediction of death by cardiovascular related events in a German population-based study cohort

A simple equation established by Cordova &; Cordova (LDL-COR) was developed to provide an improved estimation of LDL-cholesterol in a large Brazilian laboratory database. We evaluated this new equation in a general population cohort in Pomerania, north-eastern Germany (SHIP Study) compared to other existing formulas (Anandaraja, Teerakanchana, Chen, Hattori, Martin, Friedewald and Ahmadi), and its power in the prediction of death by atherosclerosis related events as the primary outcome. Analysis was conducted on a cohort of 4075 individuals considering age, gender, use of lipid lowering therapy and associated co-morbidities such as diabetes, hepatic, kidney and thyroid disease. LDL-COR values had a lower standard deviation compared to the previously published equations: 0.92 versus 1.02, 1.02, 1.03, 1.04, 1.09, 1.10 and 1.74?mmol/L, respectively. All of the factors known to affect the results obtained by the Friedewald’s equation (LDL-FW), except fibrate use, were associated with the difference between LDL-COR and LDL-FW (p?p?=?.06). LDL-COR determined a higher hazard ratio (1.23 versus 1.12, 1.19, 1.21, 1.19, 1.21 and 1.19) for cardiovascular disease related mortality, incident stroke or myocardial infarction compared to the other evaluated formulas, except for Ahmadi’s (1.24), and the same adjusted predictive power considering all confounding factors. The proposed simple equation was demonstrated to be suitable for a more precise LDL-c estimation in the studied population. Since LDL-c is a parameter frequently requested by medical laboratories in clinical routine, and will probably remain so, precise methods for its estimation are needed when direct measurement is not available.     

The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials

AimsTo systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines.Data synthesisFrom inception through June 2019, we searched PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for guidelines, systematic reviews, and RCTs (for coffee intake only) of at least 13 days duration. Additionally, we searched Trip database for guidelines from 2009 through Oct 2019. Language was restricted to English. The strength of evidence was evaluated using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 37 guidelines, 108 systematic reviews, and 20 RCTs were included. With high evidence, foods high in unsaturated and low in saturated and trans fatty acids (e.g. rapeseed/canola oil), with added plant sterols/stanols, and high in soluble fiber (e.g. oats, barley, and psyllium) caused at least moderate (i.e. 0.20–0.40 mmol/L) reductions in LDL cholesterol. Unfiltered coffee caused a moderate to large increase. Soy protein, tomatoes, flaxseeds, and almonds caused small reductions. With moderate evidence, avocados and turmeric caused moderate to large reductions. Pulses, hazelnuts, walnuts, high-fiber/wholegrain foods, and green tea caused small to moderate reductions, whereas sugar caused a small increase. Other identified foods were either neutral or had low or very low evidence regarding their effects.ConclusionsSeveral foods distinctly modify LDL cholesterol levels. The results may aid future guidelines and dietary advice for hypercholesterolemia.     

LDL subclasses in IDDM patients: relation to diabetic nephropathy

Summary To answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric [AER 7 (1–19) g/min, median and range], in 46 microalbuminuric [AER 50 (20–192) g/min] and in 33 proteinuric [AER 422 (233–1756) g/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger LDL particles than non-diabetic control subjects (260 Å vs 254 Å, p<0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p<0.05 for normoalbuminuric and p<0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p<0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p<0.05 for both) was mainly due to the increment of light LDL (density 1.0212–1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles. The prevalence of atherogenic small dense LDL particles in IDDM patients with microalbuminuria and proteinuria is closely dependent on plasma triglyceride concentration.Abbreviations AER urinary album excretion rate - CETP cholesteryl ester transfer protein - IDDM insulin-dependent diabetes mellitus - CHD coronary heart disease - ApoB apolipoprotein B     

Simvastatin reduces plasma concentration of high-sensitivity C-reactive protein in type 2 diabetic patients with hyperlipidemia

High-sensitivity C-reactive protein (hs-CRP) is positively associated with the prevalence of coronary artery disease by epidemiologic data. Prospective studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced the plasma hs-CRP concentration and the risk of recurrent coronary events after myocardial infarction. Type 2 diabetes is associated with high mortality risk of coronary heart disease and this high risk may be involved in the inflammatory factors. We have therefore conducted a prospective study to assess whether simvastatin can rapidly reduce the plasma hs-CRP concentration in type 2 diabetic patients with hyperlipidemia. Seventeen type 2 diabetic patients with hyperlipidemia were enrolled in the study after 6 weeks on a lipid-lowering diet. Fourteen patients completed the study, taking simvastatin 20 mg daily for 8 weeks. Fasting blood samples were collected from each patient before and after 8-week administration of simvastatin. In response to 8-week administration of simvastatin, hs-CRP levels significantly decreased from 0.312±0.057 to 0.193±0.045 mg/dl (P<.01). Plasma LDL cholesterol also decreased significantly from 130±9 to 74±3 mg/dl (P=.001). This study shows that plasma hs-CRP concentration can be reduced by 8-week administration of simvastatin in type 2 diabetic patients with hyperlipidemia.     

Clinical significance of the physicochemical properties of LDL in type 2 diabetes

Atherosclerosis is the leading cause of death in type 2 diabetes. LDL cholesterol and atherosclerosis are related, both in healthy people and those with diabetes; however, people with diabetes are more prone to atheroma, even though their LDL cholesterol levels are similar to those in their non-diabetic peers. This is because LDL particles are modified in the presence of diabetes to become more atherogenic. These modifications include glycation in response to high plasma glucose levels; oxidative reactions mediated by increased oxidative stress; and transfer of cholesterol ester, which makes the particles smaller and denser. The latter modification is strongly associated with hypertriglyceridaemia. Oxidatively and non-oxidatively modified LDL is involved in plaque formation, and may thus contribute to the accelerated atherosclerosis. This review discusses the techniques currently used to determine the physicochemical properties of LDL, and examines the evidence that modification of these properties plays a role in the accelerated atherosclerosis associated with type 2 diabetes.     

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men

Aims/hypothesis Type 1 diabetic subjects are at increased risk of cardiovascular disease and exhibit multiple qualitative abnormalities of apolipoprotein (apo) B100-containing lipoproteins. This stable isotope kinetic experiment was designed to study whether these abnormalities are associated with changes in the synthesis and fractional catabolic rates of VLDL-, IDL- and LDL-apoB100.Methods Using a bolus followed by a 16-h constant infusion of ¹³C-leucine, we performed a kinetic study in eight men with type 1 diabetes treated with a continuous subcutaneous insulin infusion administered by an external pump and in seven healthy men, in the fed state.Results The mean HbA₁c level in the type 1 diabetic patients was 8.00±1.48%. Plasma triglyceride, and total, LDL and HDL cholesterol levels were similar in patients and control subjects. VLDL were less triglyceride rich in type 1 diabetic patients than in control subjects (VLDL triglyceride : apoB 6.91±0.81 vs 8.29±1.24 mmol/g, p=0.05). Conversely, the IDL and LDL of the type 1 diabetic patients contained relatively higher levels of triglycerides (IDL triglycerides : apoB 2.16±0.36 vs 1.57±0.30 mmol/g, p<0.01; LDL triglycerides : apoB 0.27±0.06 vs 0.16±0.04 mmol/g, p<0.05). The apoB100 pool size, production and fractional catabolic rates in the two groups of subjects were similar for all lipoprotein fractions.Conclusions/interpretation Despite qualitative abnormalities, especially abnormalities of triglyceride content, the metabolism of apoB100-containing lipoproteins is not altered in type 1 diabetic men with fair glycaemic control with continuous subcutaneous insulin infusion. The high risk of atherosclerosis in these patients cannot be explained by kinetic abnormalities of apoB100-containing lipoproteins.     

Glycosylation enhances oxygen radical-induced modifications and decreases acetylhydrolase activity of human low density lipoprotein

Background. Posttranslational nonenzymatic glycosylation of native low-density lipoprotein (n-LDL) occurs bothin vitro andin vivo in diabetic patients. Glycosylated LDL (glc-LDL) behave similarly to oxidized LDL in some respects. In fact, unlike n-LDL, uptake of glc-LDL can occur in part by the scavenger receptor(s), as also demonstrated for oxidized LDL. The enzyme acetylhydrolase, carried by LDL, catabolizes platelet activating factor (PAF). This enzymatic activity is inhibited in oxidized LDL. However, it is unknown whether glc-LDL have reduced acetylhydrolase activity.Objectives. The first aim of the study was to investigate whether glc-LDL were more susceptible than n-LDL to oxidative modification, and which different oxygen radical species were involved in the phenomenon. Moreover, in order to investigate whether glycosylation may affect acetylhydrolase, we also measured this enzymatic activity in both n- and glc-LDL.Methods. In vitro glc-LDL and n-LDL were exposed to the oxidants xanthine/xanthine oxidase (X/XO; 2 mM and 100 mU/ml, respectively), or CuSO₄ (10 M) for 18 hs at 37°C. Parallel experiments were done in the presence of the superoxide radical scavenger superoxide dismutase (SOD; 330 U/ml), the hydrogen peroxide scavenger catalase (1000 U/ml), or the hydroxyl radical scavenger dimethylthiourea (10 mM) or dimethylsulfoxide (1 mM). Standards of PAF and lyso-PAF were visualized with iodine vapors after separation by thin layer chromatography. The distribution of label was determined by an imaging scanner. Labeled products were then isolated from the chromatography plate, and the amount of³H-lyso-PAF formed was determined by liquid scintillation counting.Results. Glc-LDL were more susceptible than n-LDL to lipid peroxidation (n-LDL 22.9±3.4 vs 34.8±4.2^* nmoles/MDA/mg of protein in glc-LDL oxidized by X/XO and n-LDL 28.9±4.2 vs 40.4±4.1^* in glc-LDL oxidized by CuSO₄,^*p<0.05 vs n-LDL). SOD, but not other scavengers, prevented peroxidation, indicating an obligatory role for superoxide radicals. Oxidation of glc-LDL also induced a higher degree of apolipoprotein-B₁₀₀ modifications than n-LDL, with increased electrophoresis mobility and decreased TNBS reactivity. These effects were similarly prevented by SOD. Finally, acetylhydrolase activity was significantly lower in glc-LDL than in n-LDL.Conclusion. Glycosylation increases LDL oxidation due to superoxide radicals, and also reduces acetylhydrolase activity. These phenomenona may contribute to enhance and/or accelerate the progression of atherosclerosis in diabetic patients.Abbreviation LDL low density lipoprotein - n-LDL native LDL - glc-LDL glycosylated LDL - PAF platelet activating factor - X/XO xanthine/xanthine oxidase reaction - SOD superoxide dismutase - DMTU dimethylthiourea - DMSO dimethylsulfoxide - TNBS trinitrobenzenesulfonic acid - MDA malonyldialdehyde - LPO lipid peroxides This study was presented in abstract form at the 42nd Annual Scientific Session of the American College of Cardiology, Anaheim, CA, 14–18 March 1993 (see Ref. 30).     

冠心病患者血浆纤维蛋白原与小而密低密度脂蛋白的关系

目的　探讨血浆纤维蛋白原 (Fib)水平升高和小而密低密度脂蛋白 (sLDL)在冠心病发病中的作用及两者的关系。方法　采用Clauss法测定 2 3 4例经冠状动脉造影证实为冠心病的患者及164例经冠状动脉造影证实无冠状动脉病变的对照者血浆Fib水平 ,以密度梯度聚丙烯酰胺凝胶电泳法测定sLDL在低密度脂蛋白中所占的比例 ,同时检测血清胆固醇 (TC)、甘油三酯 (TG)、低密度脂蛋白胆固醇 (LDL C)、高密度脂蛋白胆固醇 (HDL C)水平。根据冠状动脉造影的结果将冠心病组分为 1支、2支和 3支病变组 ,观察其与Fib及sLDL的关系。结果　冠心病组血浆Fib及血脂水平明显高于对照组 (HDL C低于对照组 ) ,P <0 0 5,Fib与sLDL水平随冠状动脉病变支数增加而升高 (P <0 0 5)。sLDL与冠状动脉病变程度密切相关 (r =0 452 ,P <0 0 0 1) ,与Fib水平呈正相关 (y =4 17x + 4 4 67)。结论　sLDL是冠心病发病的独立危险因素 ,Fib与sLDL呈正相关 ,Fib可能间接地对冠心病发病起一定作用     

Lipoprotein(a): Pathophysiology,measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d’Athérosclérose (NSFA)

Central Illustration. Pathophysiological pathways providing a causal link between high plasma concentrations of lipoprotein(a) (Lp(a)) and atherosclerotic vascular disease and aortic valve stenosis (AVS). Clinical outcomes are related to accelerated atherosclerosis complicated by atherothrombosis (myocardial infarction, stroke), peripheral artery disease (PAD) or aortic valve replacement (AVR) caused by valve calcification and aortic stenosis. Apo(a): apolipoprotein(a); LDL: low-density lipoprotein; OxPL: oxidized phospholipids; NSFA: Nouvelle Société Francophone d’Athérosclérose; SP: serine-protease domain; V: plasminogen kringle V (reproduced with permission).